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A Phase 0 clinical trial is a new idea from the US Food and Drug Administration and the Pharmaceutical Research and Manufacturers of America (PhRMA) that both organizations say they hope will streamline the process of drug development.

With Phase 0 trials needing fewer preclinical studies than are usually required for a Phase I trial, researchers would give a few volunteers less than 1% of the therapeutic dose of an investigational drug, a microdose, thus necessitating manufacture of smaller batches. The trial would take no more than seven days, and the greatly reduced dose would ensure the absence of toxic effects.

The new program is one of the changes promised by FDA in its Critical Path Initiative, the effort to modernize and speed up the clinical trials process. The official name of a Phase 0 trial is an exploratory investigational new drug (IND) study, and the goal is to quickly establish whether an agent will work as desired in humans. The theory is that such a trial should also quickly weed out ineffective drugs.

These two factors are intended to give pharmaceutical companies faster answers about whether to move forward with regular clinical trials.

A major impetus for Phase 0 is a clogged drug pipeline: Only 20 new drugs were approved in 2005, compared with 36 in 2004 and 53 in 1996.

How Phase 0 Works

Phase 0 should be able to show whether a drug's pharmacokinetics and pharmacodynamics warrant continued exploration. For example, researchers will be able to tell if the drug is entering the bloodstream as it should or interacting with a certain enzyme as anticipated.

The process will not demonstrate a therapeutic effect, nor will it replace the dose escalation, safety, and tolerance studies required in Phase I.

Then, what's the point? Phase 0 can eliminate drugs that don't measure up to even the most rudimentary requirements, and thus can save time and money, said David Jacobson-Kram, PhD, Associate Director of Pharmacology and Toxicology in the FDA's Office of New Drugs.

“Most agents fail clinical testing because they don't behave as predicted in animal studies, and far too many drugs fail late in development.”

“We met with FDA two years ago and discussed the idea as a way to improve decision making about whether to go ahead with clinical trials,” Dr. Goldhammer said. “We think it will save time, money, and other resources.”

He also said that many pharmaceutical companies have expressed “keen interest” about Phase 0, but when asked which companies are actually using it, Dr. Goldhammer said that he had done no follow-up.

Many Researchers Skeptical

“This is a cosmetic thing for FDA—a look-good, feel-good move,” said Richard L. Schilsky, MD, Professor of Medicine and Associate Dean for Clinical Research at the University of Chicago and Chairman of Cancer and Leukemia Group B.

“It appears to address a need that some people perceive, and we do need further scientific advances because we don't fully understand tumorigenesis, but Phase 0 is clearly not the major retooling that we have been waiting for.

“Phase 0 might be good for a limited class of agents like biologicals because fewer resources would be needed for preclinical work,” Dr. Schilsky continued. “But by and large, most drug companies I've spoken with are not enthusiastic. They think it's better to do a full Phase I trial.”

Dr. Jacobson-Kram acknowledged that reaction from the research community has been slow. Although FDA is not yet able to track applications for Phase 0 trials, he said he thinks that few have been submitted.

Objections

▪ A microdose of a drug or targeted agent may not provide the information needed to judge efficacy, especially without a biomarker to predict tumor activity.

▪ Even if a Phase 0 trial is successful, a full IND application, with the usual three pre-approval phases, is still required.

▪ Although both healthy volunteers and cancer patients can be subjects, they may not be willing to take a tiny dose of a drug that has no therapeutic benefit. Still, Dr. Jacobson-Kram maintained that it should be no more difficult to recruit patients to a Phase 0 trial than for any other.

▪ Some researchers say that it will not save either time or money when testing targeted therapies because no one knows enough about how such drugs work in order to determine what, if anything, can be learned from Phase 0. Dr. Jacobson-Kram countered by saying that it will be possible to see how well an agent is hitting its target, but not how well it is modulated. “But step one is to hit the target,” he said.

Dr. Schilsky thought that recruiting subjects will be a real obstacle. “You probably could use healthy volunteers, but they may not be truly representative of the problem [the cancer] at hand, and I think it would be hard to find cancer patients willing to take a microdose of a ‘useless’ drug.

“If there were a way to seamlessly link Phase 0 with Phase I in a relatively short time—not the year or two that it usually takes—that might be something to think about. But, really, it's only a theoretical possibility, not a practical goal.”

Mace Rothenberg, MD, Professor of Cancer Research at Vanderbilt-Ingram Cancer Center, commented, “In oncology, we don't have either a biological or pharmacological assay to measure whether a drug is hitting the target and having a therapeutic effect. For this reason, many drugs will fail Phase 0, and we could misidentify active drugs as inactive.” False negative results from a Phase 0 trial is a significant potential problem

Dr. Schilsky agreed: “The goal here is not to have a clinical effect, and you may not even be able to tell if there is a biological response. But if there is one, it doesn't necessarily mean anything. For an agent to hit its biological target is necessary but insufficient.”

FDA Guidance

FDA's Dr. Jacobson-Kram acknowledged the problems. He said that an exploratory IND won't revolutionize drug development, but it's a useful technique.

The FDA guidance on the subject was issued in January. A guidance is a document of suggestions and does not hold the force of regulatory law. This particular one explains that, “existing regulations allow a great deal of flexibility in the amount of data that needs to be submitted with an IND application” and that “the Agency believes that sponsors have not taken full advantage of that flexibility and often provide more supporting information in INDs than is required.”

In this guidance, FDA appears to be encouraging more versatility than it is usually given credit for and said that an exploratory IND can help sponsors in the ways described above.

Because Phase 0 studies use either a subpharmacologic dose or a dose that produces a pharmacologic but not a toxic effect, the risk to human subjects is far less than in Phase I to establish maximum tolerated dose.

The guidance goes on to say that exploratory INDs can be used in drugs for any indication, but it is particularly important for manufacturers to consider them when developing drugs for serious diseases.